When research does not require FDA approval, there may be no oversight at all. Companies can conduct preliminary studies of drugs in poor countries before formal testing even begins. Quite literally, the participants in their studies are used as guinea pigs, subjects of research that really should be done on experimental animals. That was the case in le Carré’s fictional account. Although some research in the US and other wealthy countries also escapes formal oversight, there are generally more restrictions on what researchers can get away with.
Several real third-world clinical trials were described in detail in a six-part Washington Post series in 2000, called “The Body Hunters.” One of them has parallels to le Carré’s story. In 1996, Nigeria was in the grip of a widespread epidemic of bacterial meningitis, which eventually claimed over 15,000 lives. Pfizer, the world’s biggest drug company, was at that time conducting the largest research program it had ever undertaken to get FDA approval for a new antibiotic called Trovan. Eventually the drug was tested on 13,000 people in twenty-seven countries. When one of Pfizer’s doctors heard about the epidemic in Nigeria, he immediately got approval from Nigerian authorities to bring a team to Kano, a city of two million people in northern Nigeria, to test Trovan in children with meningitis. The aim was to demonstrate that oral Trovan would work as well in these children as an established fast-acting intravenous antibiotic.
Within six weeks, the Pfizer team had set up its program in the squalid Kano Infectious Diseases Hospital at the center of the epidemic. A local doctor was named as principal investigator, and the team rapidly enrolled two hundred children for the study. Half were given Trovan, many of them in pill or drink form. The other half were given injections of ceftriaxone, an antibiotic known to be effective against epidemic meningitis. Two weeks later, at the end of the trial, an equal number of children had died in both groups. The new drug was apparently just as effective as the old one, and it could be given in oral form. On that basis, Pfizer applied to the FDA for approval to market oral Trovan for use in children with meningitis.
Those are the bare outlines of what happened. But critics such as Médecins Sans Frontières, the Nobel Prize– winning international medical relief organization, charge that this was exactly the sort of study that would not have been permitted in the Uni-ted States. To these critics, it was unethical to test an experimental drug orally in the midst of an epidemic. The usual treatment for meningitis in such urgent conditions would be intravenous antibiotics. In fact, the Pfizer doctor who organized the study told The Washington Post that antibiotics “would never be used like that in the United States. The standard is IV therapy.” It was also charged that there had not been adequate preliminary research into how Trovan is absorbed and metabolized by children or how effective it is against meningitis.
Furthermore, to lessen the pain of injections, the dose of intravenous ceftriaxone given for comparison was much smaller than originally planned. But if the dose of the comparison drug were inadequate, that would make Trovan look better than if it were compared with a full dose of ceftriaxone. Pfizer maintained that the smaller dose was still more than sufficient, but the medical director of Hoffmann-La Roche, the manufacturer of ceftriaxone, was quoted as saying, “A high dose is essential.”
Questions were also raised about whether the subjects had given informed consent and whether an ethics committee had approved the trial. The families did not sign informed consent documents, but the company maintained they had consented orally. However, some doctors and family members disputed this. A laboratory technician in Kano said, “The patients did not know if it was research or not. They just knew they were sick.”
Even more troubling was the issue of ethics committee approval. A Pfizer spokeswoman told The Washington Post that the research had been approved by a Nigerian ethics board. But a month later, the Post found that the lead Nigerian researcher admitted to creating and backdating the approval document. According to the Post, the document was typed on the letterhead of the Aminu Kano Teaching Hospital and dated March 28, 1996 (six days before the trial began), but the researcher said that he actually wrote it about a year later. Pfizer reportedly gave the document to the FDA in 1997 during an audit of records supporting its application for approval of Trovan. The hospital’s medical director told the Post the document was “a lie.” In fact, he said, the hospital didn’t even have an ethics board at the time the trial was done.
In 1997, Trovan was approved by the FDA to treat certain infections, but not for children and not for epidemic meningi-tis. The FDA found dozens of discrepancies in the documents from Nigeria. Trovan quickly became a highly profitable antibiotic widely used against a variety of infections. However, after less than two years on the market, there were over a hundred reports that the drug produced liver toxicity, causing several deaths, and it is no longer sold.
In 2001, the families of thirty Nigerian children who either died or suffered serious injury in the Kano trial filed suit against Pfizer in a New York federal district court. They alleged that the company increased the risk of death and injury by failing to provide a treatment of proven efficacy for children who did not respond to Trovan and by giving the patients used for comparison a weakened version of ceftriaxone. They also complained that they had not given informed consent. According to the complaint,
Pfizer took the opportunity presented by the chaos caused by the civil and medical crises in Kano to accomplish what the company could not do elsewhere—to quickly conduct on young children a test of a potentially dangerous antibiotic.
During the following four years, Pfizer argued that the case should not be heard in a US court at all. In August of this year, Southern District of New York Judge William H. Pauley III agreed, ruling that Nigeria, not the US, was the proper place to try a lawsuit over Pfizer’s conduct of the Trovan trial. The families plan to appeal.
Drug companies are not the only sponsors of research in the third world that wouldn’t be allowed at home. In the 1990s, two government agencies, the National Institutes of Health (NIH) and the Centers for Disease Control (CDC), sponsored some nine clinical trials in the third world in which thousands of HIV-infected pregnant women under study were given a placebo (or sugar pill) instead of the drug AZT, even though the latter had been shown to cut by 70 percent the risk of transmission of HIV/AIDS from mother to infant. The aim of the studies was to see whether a shorter, simpler course of treatment might be as effective. The standard course required taking oral AZT for the last trimester of pregnancy, an intravenous infusion of the drug during labor and delivery, and oral treatment of the newborn for six weeks. There was preliminary evidence that oral treatment limited to the last few weeks of pregnancy and the first few days of the newborn’s life might also be effective.
But instead of comparing the transmission rate in women who received an experimental short course of treatment with that in women receiving the standard course, the researchers compared it with the transmission rate in women who received only a placebo—thus consigning many babies in their care to be born with HIV/AIDS that could have been prevented. This was justified as being the fastest way to show whether a short course was reasonably effective, but designing the trials in that way certainly wasn’t scientifically necessary, and, in any case, it would never have been permitted in the US.
In 1997, in an article in The New England Journal of Medicine, Peter Lurie and Sidney M. Wolfe of Public Citizen’s Health Research Group protested that the trials should have compared short courses of treatment with the standard long one, not a placebo.2 As executive editor of the Journal, I wrote an accompanying editorial in support of their view (“The Ethics of Clinical Research in the Third World”). The public reaction was intense. Many in the US research establishment, including the directors of the NIH and CDC, vigorously defended the trials, pointing out that the women denied AZT probably wouldn’t have been able to obtain it where they lived anyway. But that argument, which was meant to mitigate criticism of the trials, simply underscored the fact that the NIH and CDC were willing to take advantage of the women’s poverty and vulnerability. The researchers could easily have supplied the drug to all the women they enrolled (and for whom they thereby assumed responsibility), even if it wasn’t widely available in the region.3
Some writers who comment on medical ethics are not so much concerned with the design and conduct of particular trials in the third world as with the legitimacy of carrying on research there in the first place. They believe it is virtually impossible to conduct medical research ethically in poor countries, because it is inherently exploitative. Although this seems to me too broad a judgment, I believe the amount of research sponsored by the first world in the third world should be sharply curtailed. It is driven too much by the search for profits. It offers quick answers precisely because it is so easy to cut corners.
Before a study is exported to the third world, two important questions should be asked. First, would it be possible to do the research in the first world? And second, why is it being diverted to poor countries? It is sometimes claimed that research should be done where health needs are greatest—and that is certainly the case in the third world. But this view confuses research with treatment. There is a great need to apply the results of research, wherever it is conducted, to the treatment of people in the third world. Unfortunately, that is not what happens. Research findings are applied predominantly in well-to-do countries even when the research is done in poor ones. The only clinical research that clearly needs to be conducted in the third world is research on third-world diseases. Such work is amply justified, and far more of it is needed. Unfortunately, it is not a high priority either for the pharmaceutical industry or the National Institutes of Health.
In my view, research should not be done in the third world unless it concerns diseases that are virtually confined to those regions. And regulations governing research in poor countries should be every bit as stringent—and enforced just as vigilantly—as in well-to-do countries. There is no justification for the present situation in which the standards are looser precisely where human subjects are most vulnerable.
Before research on human subjects is undertaken anywhere in the world, there should be adequate animal studies and preliminary tests on normal subjects to eliminate all unnecessary risks. Consent should be truly informed, and there should be no penalties for refusing to participate or undue inducements to do so. It is not enough to claim that informed consent was oral. It should be documented. If there is any doubt about whether the information given to subjects was understood, subjects should be asked to repeat their understanding of the research. To be on the safe side, that conversation and their consent could be videotaped. Companies should no longer be allowed to conduct research in the third world that they would not be permitted to do at home.
Le Carré seems bleak about the chances of any such reform. At the end of the novel, both Quayles are dead, no one is called to account, and KVH and all the people who serve its interests in and out of government presumably continue undeterred. The film, however, adds a Hollywood-style hint of justice to come. At Justin’s funeral in London, Tessa’s cousin, in whom she had confided, reveals in a eulogy for the couple just why they were killed. Reporters scribble in their notebooks and race for phones, while Sir Bernard Pellegrin, the unctuous and complicit director of affairs for Africa of the British Foreign Office, looks increasingly uneasy and finally flees in consternation. In adding this unlikely scene, the film writers did a disservice to le Carré’s book, but that is a small fault. The larger one is in not making it clear, as le Carré did so well, exactly what Tessa Quayle was unhappy about.
"Unethical Trials of Interventions to Reduce Perinatal Transmission of the Human Immunodeficiency Virus in Developing Countries," The New England Journal of Medicine, September 18, 1997.↩
“Unethical Trials of Interventions to Reduce Perinatal Transmission of the Human Immunodeficiency Virus in Developing Countries,” The New England Journal of Medicine, September 18, 1997.↩